Lp(a) is a highly atherogenic lipid fraction with numerous studies showing a strong association between elevated Lp(a) and coronary artery disease stroke and aortic stenosis. |
The expression of Lp(a) is largely determined by autosomal dominant inheritance with behavioral factors having minimal influence over serum levels. |
Persons of African and South Asian descent have significantly higher mean Lp(a) levels than persons of European Latin American or East Asian descent. |
Novel therapies including PCSK-9 inhibitors and antisense oligonucleotides significantly reduce Lp(a) levels independently of LDL reductions. |
Further studies on the role of Lp(a) reduction in primary cardiovascular disease prevention are needed. |
Introduction
What is Lipoprotein(a)?
Authors and year | Title | Study population | Main intervention | Endpoints | Results |
---|---|---|---|---|---|
Frick et al. (1978) | Serum lipids in angiographically assessed coronary atherosclerosis | 153 Scandinavian men and women who underwent preoperative evaluation of coronary arterial anatomy for subsequent bypass surgery, or evaluation of angina-like chest pain combined with abnormal resting and/or exercise electrocardiogram | Comprehensive lipid analysis in a series of patients with angiographic assessment of coronary atherosclerosis which was subjected to segmental grading | Coronary atherosclerosis | Cholesterol (p < 0.05), positivity of Lp (a)/pre-beta1 lipoprotein (p < 0.01), a family history of coronary heart disease (p < 0.05), and smoking (p < 0.01) differed between the group of normal arteries and the whole group of luminal obstructions. Serum triglycerides were not associated with coronary atherosclerosis. Cholesterol, positivity of the Lp(a)/pre-beta1 lipoprotein and a family history of coronary heart disease were also associated with the severity of the disease |
Sandholzer et al. (1991) | Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups | 279 Tyrolean subjects, 105 Sudanese, 143 Indian, 125 Malaysian, 112 Chinese, 202 Hungarian, 184 Icelandic | Lp(a) concentrations and apo(a) phenotypes were determined in 7 ethnic groups | Lp(a) level by ethnic group | Average Lp(a) concentrations were highly significantly different among these populations, with the Chinese (7.0 mg/dl) having the lowest and the Sudanese (46 mg/dl) the highest levels. Apo(a) phenotype and derived apo(a) allele frequencies were also significantly different among the populations. Apo(a) isoform effects on Lp(a) levels were not significantly different among populations. Lp(a) levels were however roughly twice as high in the same phenotypes in the Indians, and several times as high in the Sudanese, compared with Caucasians. The size variation of apo(a) explains from 0.77 (Malays) to only 0.19 (Sudanese) of the total variability in Lp(a) levels |
Virani et al. (2012) [55] | Associations between lipoprotein(a) levels and cardiovascular outcomes in African Americans and Caucasians: The Atherosclerosis Risk in Communities (ARIC) Study | 3467 African Americans and 9851 Caucasians, representative of adults aged 45–64 years living in 4 communities in the United States between 1987 and 1989 | Plasma Lp(a) was measured in African Americans and Caucasians | CHD and stroke | Adjusted HRs (95% confidence interval [CI]) per race-specific 1-SD–greater log-transformed Lp(a) were 1.13 (1.04–1.23) for incident CVD, 1.11 (1.00–1.22) for incident CHD, and 1.21 (1.06–1.39) for ischemic strokes in African Americans. For Caucasians, the respective HRs (95% CIs) were 1.09 (1.04–1.15), 1.10 (1.05–1.16), and 1.07 (0.97–1.19). Quintile analyses showed that risk for incident CVD was graded but statistically significant only for the highest compared with the lowest quintile (HR [95% CI] 1.35 [1.06–1.74] for African Americans; HR 1.27 [1.10–1.47] for Caucasians) |
Tsimikas et al. (2015) | Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study | Healthy ethnically heterogeneous adults (60% white 17% black, 15% Asian, 6% Other) aged 18–65 years, with body-mass index (BMI) less than 32.0 kg/m2 and Lp(a) concentration of 25 nmol/l (100 mg/l) or more | Single subcutaneous injection of ISIS-APO(a)Rx (50 mg, 100 mg, 200 mg, or 400 mg) or placebo (3:1) in the single-dose part of the study or to receive six subcutaneous injections of ISIS-APO(a)Rx (100 mg, 200 mg, or 300 mg, for a total dose exposure of 600 mg, 1200 mg, or 1800 mg) or placebo (4:1) during a 4-week period in the multi-dose part of the study | Lp(a) level | Whereas single doses of ISIS-APO(a)Rx (50–400 mg) did not decrease Lp(a) concentrations at day 30, six doses of ISIS-APO(a)Rx (100–300 mg) resulted in dose-dependent, mean percentage decreases in plasma Lp(a) concentration of 39.6% from baseline in the 100 mg group (p = 0.005), 59.0% in the 200 mg group (p = 0.001), and 77.8% in the 300 mg group (p = 0.001). Similar reductions were observed in the amount of oxidized phospholipids associated with apolipoprotein B-100 and apolipoprotein(a) |
O’Donoghue et al. 2019 | Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk | 27,564 patients (78% white) between 40 and 85 years of age who had established atherosclerotic CV disease, determined by a prior myocardial infarction (MI), prior nonhemorrhagic stroke, or symptomatic peripheral artery disease, in addition to predictors of high CV risk. No entry criteria for Lp(a) | Randomized double-blind controlled trial of evolocumab versus placebo | Coronary heart disease death, myocardial infarction, or urgent revascularization; Lp(a) reduction | At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2–46.7%). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67–0.88) in patients with a baseline Lp(a) > median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80–1.08; P interaction = 0.07) in those ≤ median |
Tsimikas et al. 2019 | Statin therapy increases lipoprotein(a) levels | Six randomized trials (Miracle, Children with FH, Astronomer, Prove-It, Reversal, Vision) with a total of 5256 patients | Subject-level meta-analysis | Change in Lp(a) level | In the statin-vs.-placebo pooled analysis, the ratio of geometric means [95% confidence interval (CI)] for statin to placebo is 1.11 (1.07–1.14) (p < 0.0001), with ratio > 1 indicating a higher increase in Lp(a) from baseline in statin vs. placebo. The mean percent change from baseline ranged from 8.5% to 19.6% in the statin groups and − 0.4% to − 2.3% in the placebo groups. In the statin-vs.-statin pooled analysis, the ratio of geometric means (95% CI) for atorvastatin to pravastatin is 1.09 (1.05–1.14) (p < 0.0001). The mean percent change from baseline ranged from 11.6% to 20.4% in the pravastatin group and 18.7% to 24.2% in the atorvastatin group. Incubation of HepG2 hepatocytes with atorvastatin showed an increase in expression of LPA mRNA and apolipoprotein(a) protein |
Gudbjartsson et al. (2019) [31] | Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes | 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8734 with T2D | Mendelian randomization; This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk | Cardiovascular disease incidence and prevalence; incident and prevalent type 2 diabetes mellitus | Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D |
Langsted et al. (2019) [29] | High lipoprotein(a) and high risk of mortality | Danish general population, of which 69,764 had information on lipoprotein(a) concentrations, 98,810 on LPA kringle-IV type 2 (KIV-2) number of repeats, and 119,094 on LPA rs10455872 genotype | Mendelian randomization of Lp(a) allele and serum concentration | Cardiovascular and all-cause mortality | Observationally, lipoprotein(a) > 93 mg/dl (199 nmol/l; 96th-100th percentiles) vs. < 10 mg/dl (18 nmol/l; 1st-50th percentiles) were associated with a hazard ratio of 1.50 (95% confidence interval 1.28–1.76) for cardiovascular mortality and of 1.20 (1.10–1.30) for all-cause mortality. The median survival for individuals with lipoprotein(a) > 93 mg/dl (199 nmol/l; 96th-100th percentiles) and ≤ 93 mg/dl (199 nmol/l; 1st-95th percentiles) were 83.9 and 85.1 years (log rank P = 0.005). For cardiovascular mortality, a 50 mg/dl (105 nmol/l) increase in lipoprotein(a) levels was associated observationally with a hazard ratio of 1.16 (1.09–1.23), and genetically with risk ratios of 1.23 (1.08-1.41) based on LPA KIV2 and of 0.98 (0.88–1.09) based on LPA rs10455872. For all-cause mortality, corresponding values were 1.05 (1.01–1.09), 1.10 (1.04–1.18), and 0.97 (0.92–1.02), respectively |
Langsted et al. 2019 | Elevated lipoprotein(a) and risk of ischemic stroke | 49,699 individuals from the Copenhagen General Population Study and 10,813 individuals from the Copenhagen City Heart Study with measurements of plasma lipoprotein(a), LPA kringle-IV type 2 number of repeats, and LPA rs10455872 | Mendelian randomization of Lp(a) allele and serum concentration | Ischemic stroke | Compared with individuals with lipoprotein(a) levels < 10 mg/dl (< 18 nmol/l: first to 50th percentile), the multivariable-adjusted hazard ratio for ischemic stroke was 1.60 (95% confidence interval [CI]:1.24 to 2.05) for individuals with lipoprotein(a) levels > 93 mg/dl (> 199 nmol/l: 96th to 100th percentile). In observational analyses for a 50 mg/dl (105 nmol/l) higher lipoprotein(a) level the age- and sex-adjusted hazard ratio for ischemic stroke was 1.20 (95% CI: 1.13 to 1.28), while the corresponding age- and sex-adjusted genetic causal risk ratio for KIV-2 number of repeats was 1.20 (95% CI: 1.02 to 1.43) and for rs10455872 was 1.27 (95% CI: 1.06 to 1.51). The highest absolute 10-year risk of ischemic stroke was 17% in active smoking individuals > 70 years of age with hypertension and lipoprotein(a) levels > 93 mg/dl (> 199 nmol/l: 96th to 100th percentile) |
Bittner et al. (2020) [69] | Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome | 18,924 (15,024 white, 473 black, 2498 Asian) patients age 40 years or older who experienced an ACS 1–12 months before randomization and who had a LDL-C level of ≥ 70 mg/dl (1.81 mmol/l), non-high-density lipoprotein cholesterol (non-HDL-C) level of ≥ 100 mg/dl (2.59 mmol/l), or an apolipoprotein B level of ≥ 80 mg/dl on high-intensity statin therapy | A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE) | Composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina that required hospitalization | Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI 0.990–0.999; p = 0.0081). Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7–59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0–13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7–67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI] 0.78–0.93) |
Associations Between Lp(a) and Cardiovascular Disease
Coronary Artery Disease
Stroke
Aortic Stenosis
Racial Differences in Lp(a) Levels and Pathogenicity
Monitoring Lp(a) in Clinical Practice
Therapeutics for Lp(a) Reduction
Therapy | Mechanism of action | Effect size | Side-effect profile | Efficacy of reducing CVD burden |
---|---|---|---|---|
Plasma apheresis | Physical separation of lipid fractions from plasma through mechanical forces | Up to 70% reduction in Lp(a) level | Fatigue, exsanguination, hypotension | Difficult to assess due to lack of controlled studies; 78% in German cohort study |
Niacin | Mechanism unknown | Up to approximately 30% reduction in Lp(a) level in highest quintile | Flushing, hyperglycemia, hyperuricemia, gastrointestinal symptoms | No clinical benefit demonstrated |
Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors | Decreased production of Apo(a) combined with increased clearance of LDL | 26.9% reduction in Lp(a) level | Injection site reactions | CHD death, MI, or urgent coronary revascularization reduced by 16% |
Antisense oligonucleotide | Recruitment of RNAse to cleave targeted RNA sequence, reducing protein expression | 80% reduction | Injection site reactions | Clinical trials ongoing to determine efficacy |